The Animal Model of Diabetic Complications Consortium Pilot & Feasibility (P&F)
Complex diseases such as diabetes and its complications are, most commonly, the result of many small gene variations, no one of which is responsible for a major portion of disease susceptibility. Recently, we have developed strategies to identify modules of co-expressed genes in that are strongly associated with disease phenotypes and which account for a major portion of phenotypic variation. As such, these network modules constitute promising new models of disease both as diagnostic criteria and as therapeutic targets. We have generated and characterized a large F2 intercross between strains BLKS and B6 on the background of the db/db mutation. Preliminary data indicate significant variations in heart and kidney pathology. To Identify the underlying genes for cardiomyopathy and nephropathy, we will perform expression array profiling of the kidneys and hearts of a subset of the F2 mice and identify transcripts whose levels correlate with clinical phenotypes (tissue histology, excreted albumin and creatinine, blood urea nitrogen, plasma creatinine, obesity, insulin levels, lipoprotein levels, blood pressure) and whose levels are regulated by quantitative trait loci (QTL) for nephropathy and cardiomyopathy. We hypothesize that we will identify genes whose expression correlates strongly with the clinical traits and whose levels are determined by clinical trait QTL. Further, we will construct gene co-expression networks and will identify modules within these networks that are associated with diabetes and its complications. We hypothesize that we will identify gene networks strongly correlated with nephropathy and cardiomyopathy that will help identify pathologic pathways and mechanisms. We will correlate these diabetes- and complication-specific modules with expression differences seen between resistant B6 db/db mice and susceptible BLKS db/db mice. Ultimately, understanding of complication-specific expression modules, will provide diagnostic models for disease susceptibility and model targets for therapeutic interventions. Given the conservation of modules we observe across species, these results will be powerful in informing diagnosis, treatment and prevention of human disease.

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